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Tumor-infiltrating lymphocytes in the immunotherapy era | Cellular & Molecular Immunology
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The clinical success of cancer immune checkpoint blockade (ICB) has refocused attention on tumor-infiltrating lymphocytes (TILs) across cancer types. The outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell responses within the tumor microenvironment. State-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and exhaustion. Many of these states are conserved across tumor types, in line with the broad responses observed clinically. Despite this homology, not all cancer types with similar TIL landscapes respond similarly to immunotherapy, highlighting the complexity of the underlying tumor-immune interactions. This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy. Thus, while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging, the search for response and prognostic biomarkers is just beginning. Within this review, we discuss recent advances in the understanding of TIL biology, their prognostic benefit, and their predictive value for therapy. The schematic representation of the tumor immune environment shows the composition and function of a tertiary lymphoid structures (TLS), who are usually found peritumorally in the stroma and/or in the invasive margin. The chemokine CXCL13, produced by CD8+ T cells, induces chemotaxis by binding to the receptor CXCR5, mainly expressed by B cells and TFH cells, and regulates the organization of B cells inside the follicles of lymphoid tissues. The TLS consists out of a T cell-rich zone containing mature dendritic cells (DCs), in close proximity to GC containing follicle like-B cells, intermingled with follicular dendritic cells (FDCs) and surrounded by plasma cells and helper-innate lymphoid cell group 3 (ILC3) at the edge of the TLS. In the optimally organized TLS immune structure, DCs, FDCs, T cells and B cells interact and activate each other, promoting a local sustained immune response including the induction of T cell effector function, antibody generation, and clonal expansion. The stroma surrounding the tumor epithelium and the invasive margin further harbors cellular immune components including NK cells, macrophages, ILC1s and ILC2s, and a nonimmune cellular component, including fibroblasts. Within the tumor epithelium ILCs, NK cells, B cells, and different T cell subsets are present, including TEX cells,-tumor-specific CD103+CD39+ TRM CTLs and CD103+CD39- bystander TRM cells. Upon ICB, both T and B cell signaling increases. TCF1-expressing TPE cells expand and differentiate into TRM cells migrating to the tumor, where they can exert their cytolytic potential. The ICB response also increases B cell receptor diversity by means of SMH and CSR and induces their clonal expansion and differentiation into advanced antibody-producing plasma cells. TLS: tertiary lymphoid structure, TFH cells: follicular helper T cells, DCs: dendritic cells, GC: germinal center, FDCs: follicular dendritic cells, ILC3: helper-innate lymphoid cell group 3, NK cells: natural killer cells, ILC1: helper-innate lymphoid cell group 1, ILC2: helper-innate lymphoid cell group 2, TEX: terminally exhausted T cells, CTLs: cytotoxic lymphocytes, TRM: tissue resident memory, ICB: immune checkpoint blockade, TCF1: transcription factor 1, TPE: progenitor STEM-like exhausted cells, SMH: somatic hypermutation, RCS: recombinant class switch
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headline:Tumor-infiltrating lymphocytes in the immunotherapy era
description:The clinical success of cancer immune checkpoint blockade (ICB) has refocused attention on tumor-infiltrating lymphocytes (TILs) across cancer types. The outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell responses within the tumor microenvironment. State-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and exhaustion. Many of these states are conserved across tumor types, in line with the broad responses observed clinically. Despite this homology, not all cancer types with similar TIL landscapes respond similarly to immunotherapy, highlighting the complexity of the underlying tumor-immune interactions. This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy. Thus, while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging, the search for response and prognostic biomarkers is just beginning. Within this review, we discuss recent advances in the understanding of TIL biology, their prognostic benefit, and their predictive value for therapy. The schematic representation of the tumor immune environment shows the composition and function of a tertiary lymphoid structures (TLS), who are usually found peritumorally in the stroma and/or in the invasive margin. The chemokine CXCL13, produced by CD8+ T cells, induces chemotaxis by binding to the receptor CXCR5, mainly expressed by B cells and TFH cells, and regulates the organization of B cells inside the follicles of lymphoid tissues. The TLS consists out of a T cell-rich zone containing mature dendritic cells (DCs), in close proximity to GC containing follicle like-B cells, intermingled with follicular dendritic cells (FDCs) and surrounded by plasma cells and helper-innate lymphoid cell group 3 (ILC3) at the edge of the TLS. In the optimally organized TLS immune structure, DCs, FDCs, T cells and B cells interact and activate each other, promoting a local sustained immune response including the induction of T cell effector function, antibody generation, and clonal expansion. The stroma surrounding the tumor epithelium and the invasive margin further harbors cellular immune components including NK cells, macrophages, ILC1s and ILC2s, and a nonimmune cellular component, including fibroblasts. Within the tumor epithelium ILCs, NK cells, B cells, and different T cell subsets are present, including TEX cells,-tumor-specific CD103+CD39+ TRM CTLs and CD103+CD39- bystander TRM cells. Upon ICB, both T and B cell signaling increases. TCF1-expressing TPE cells expand and differentiate into TRM cells migrating to the tumor, where they can exert their cytolytic potential. The ICB response also increases B cell receptor diversity by means of SMH and CSR and induces their clonal expansion and differentiation into advanced antibody-producing plasma cells. TLS: tertiary lymphoid structure, TFH cells: follicular helper T cells, DCs: dendritic cells, GC: germinal center, FDCs: follicular dendritic cells, ILC3: helper-innate lymphoid cell group 3, NK cells: natural killer cells, ILC1: helper-innate lymphoid cell group 1, ILC2: helper-innate lymphoid cell group 2, TEX: terminally exhausted T cells, CTLs: cytotoxic lymphocytes, TRM: tissue resident memory, ICB: immune checkpoint blockade, TCF1: transcription factor 1, TPE: progenitor STEM-like exhausted cells, SMH: somatic hypermutation, RCS: recombinant class switch
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Tertiary lymphoid structures
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Vaccine
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Immunology
Immunosurveillance
Tumor infiltrating lymphocytes
B cells
T cells
Tertiary lymphoid structures
immunotherapy
Biomedicine
general
Medical Microbiology
Microbiology
Antibodies
Vaccine
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